3.5.1. 4-Chlorophenylisopropylamine
The simplest of the halogenated phenylisopropylamines is 4-chlorophenylisopropylamine (79, para-chloroamphetamine, 4-CA).
It and the N-methyl homolog (80) are highly active compounds in experimental animals, producing a remarkably long-lasting depletion of brain serotonin levels (Pletscher et al., 1963) and a decrease in tryptophane hydroxylase activity (Sanders-Bush et al., 1972).
Considerable clinical application of 4-CA has been made, and it has been found effective as an antidepressant when used chronically at levels of 75 mg/day (van Praag et al., 1971; van Praag and Korf, 1976).
There are very few side effects noted and the drug is tolerated very well. However, indications of raphe-nucleus degeneration (Yunger et al., 1974) and related neurotoxicity (Harvey and McMaster, 1976) in experimental animals have discouraged further clinical study.
An unusual aspect of 4-CA metabolism is the reported conversion of the drug to oxygen-containing products. A phenolic product was identified by Parli and Schmidt (1975) as being 3-chloro-4-hydroxyphenylisopropylamine. This would seem to invoke the NIH shift as an explanation for the migration of the chloro atom. Even more remarkable is the report (Sherman and Gal, 1976) of the isolation of 3,4-dimethoxyphenylisopropylamine following the intraventricular injection of 4-CA. This represents the formation in vivo of a weak but accepted pressor and psychotomimetic. When the mechanism of its formation is understood, a chemical link may be at hand tying the simpler phenylisopropylamine stimulants to the methoxylated psychotomimetics. There were no reports from the clinical studies of 4-CA that suggested any psychotomimetic action.
3.5.2. 4-Chloro-N-methylphenylisopropylamine
The N-methyl homolog of 4-chlorophenylisopropylamine (80, para-chloromethamphetamine p-CMA, Ro 4-6861, S-33) was also found to be a potent and long-lasting depleter of brain serotonin (Fuller et al., 1965). It has been compared with methamphetamine in normal subjects (Verster and van Praag, 1970) and has been evaluated clinically in comparison with 4-CA (79) as an antidepressant (Deniker et al., 1971; van Praag et al., 1971; van Praag and Korf, 1976). Typical dosages were between 60 and 90 mg/day, administered chronically for several weeks.
There appeared to be no physical or psychic dependence developed, no cardiovascular complications, and no sleep or appetite problems. There was no mention made of mental disturbances that might be considered psychotomimetic.
The alpha,alpha-dimethylphenylethylamine homologs of p-CMA have been explored clinicaly as anorexics. 4-Chloro-alpha-alpha-dimethylphenethylamine is used therapeutically under the name of Chlorphentermine; the ortho-isomer is known as Clortermine.
3.5.3. 4-Bromo-N-methylphenylisopropylamine
The bromo-counterparts of the chlorophenylisopropylamine have been studied, but have not found extensive clinical evaluation.
The primary amine 4-bromophenylisopropylamine (4-bromoamphetamine) is, like the 4-chloro-analog 4-CA (79), a long-term depleter of serotonin in the brain (Fuller et al. (1975). The 4-fluoro analog, while still effective biochemically, is not of as long a duration of action. The N-methyl homolog of 4-bromo-phenylisopropylamine has demanded interest from a separate point of view, however. This compound, 4-bromo-N-methylphenylisopropylamine (81, V-111, p-bromomethamphetamine), has been found to give pharmacological profiles in a large number of animal species, which are indistinguishable from those shown by LSD and other psychotomimetics (Knoll et al., 1970). Although much of the literature appearing over the period from 1965 to 1975 refers to (81) as a psychotomimetic, it had apparently never been clinically assayed in man. It is now known that the compound "has no psychotomimetic effect whatsoever in humans" (Knoll, 1974, personal communication).
The high pharmacological potency of (V-111) in the biochemistry of serotonin and its apparent enhancement of learning and memory in experimental animals have maintained an active interest in it in the research area.
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